JPS63141965A - 3, 4-diphenylpiperidine derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

Detailed Description of the Invention [In the formula, Methyl, hydroxyl, 0
1-C4-alkoxy.

halo(01<4)-alkoxy, phenyloxy, phenyl-(C+<3)-alkoxy, acyloxy with up to 4 carbon atoms, nitro, 1-
N,N-dialkylamino,morpholinoma with 4 carbon atoms 7'Cf"l: C1-C4-alkylsulfonyl, or one of the radicals X and Y is hydrogen, then! and n is 1.2 or 3] is substituted with Tasis-1
fc-'td) lance-3,4-diphenylpiperidine derivatives or physiologically acceptable salts of these compounds, provided that one of the substituents X and Y is C4-C4-alkoxy, the other is hydrogen, and Excluding compounds that are.

8) Compounds according to claim 7 which exist in enantiomeric form.

9) Reducing agent for the amide functional group of pyhalidone - ■ Acts on the pyridone [wherein X, Y and n have the meanings in formula - and 7d) A process for producing the compound according to claim 7, which comprises obtaining the corresponding pyridine lysine (2) of lance stereochemistry and optionally converting the reaction product into a physiologically acceptable salt.

3 DETAILED DESCRIPTION OF THE INVENTION The present invention relates to 3,4-diphenylpiperidine, 3,4-diphenylpiperidine derivatives or physiologically acceptable salts of these compounds, the use of these compounds as medicaments, and the preparation thereof. . Furthermore, the present invention provides novel 3,4 substituted on one or both of the phenyl groups.
- diphenylpiperidine derivatives and physiologically acceptable salts thereof, and also processes for the preparation of these compounds.

There are several references in the literature regarding the classification of 3.4-diphenylpiperidines.

That is, for example, C, F, Koexsch becomes "J, Am
, 0herr1゜S Oc * J * place, 209
3-5 (j943) chemically describes 3,4-diphenylpibrodine in both its α- and β-isomers.

K, J, Fellows are “Proc, Sac,
Exptl, Biol.

Mea, J, 57.276-7 (1944) describes the local anesthetic action of the α- and β-isomers of 5,4-diphenylpivaridine in guinea pigs and rabbits.

In addition, V. Naccid “Farmacc,
Ed, Sc, j.

328(5), 399-410 (1973) 4-(3,4-dimethoxyphenyl)-3-phenylpiharicin hydrochloride and its cytostatic properties when contacted with KB cells in vitro. and cytotoxicity are described.

Cis-4-(m-aminophenyl)-5-phenylpy? IJ lysine and its preparation are C, P, KO91S
From eh etc. ζ [J, Am, Chew, Soc,
J, 66.1957 (1944).

Upon resuming research on 3.4-:,5-phenyl derivatives of pyri-lysine, the present inventor discovered pharmacological effects in animals suggesting antidepressant effects in humans, and surprisingly, They also found that this particular molecule had no psychostimulant effects at doses that showed strong effects in tests. The psychostimulant effect associated with the stimulant antidepressant effect is up to fL.
This lack of psychostimulant effect was surprising since 4-diphenyl-2-hyo has been reported for lydone.

The present invention relates to a medicament having an antidepressant effect, and in particular to a medicament having a psychostimulant effect, an antidepressant effect, and, in some cases, an analgesic effect.
a): [wherein X and Y are the same or different and hydrogen,
Halogen, 01-4-alkyl, C3-J': 6-cycloalkyl, phenyl-(C1-5)-furkyl,
trifluoromethyl, trichloromethyl, hydroxyl, C1-alkoxy, halo(c1-4)-alkoxy, phenoxy, phenyl-(C1-C3)-alkoxy, acyloxy with up to 4 carbon atoms, amino, nitro, N, N-dialkylamino, morpholino or cl- with 1 to 4 carbon atoms in each alkyl group
C4-furkylsulfonyl, n is 1, 2 or 3
] or physiologically acceptable salts of these compounds.

Metal compounds can exist in racemic or enantiomeric form.

When n represents 2 or 3, the substituents on the particular nucleus may be the same or different.

Alkyl and alkoxy groups may be straight chain or branched.

The pharmaceutical composition may be in a suitable form for oral, rectal or parenteral administration, such as capsules, tablets, etc.
It can be in the form of granules, capsules or aqueous solutions, syrups or drinkable suspensions. The formulations contain the active compound in free form or in the form of a physiologically acceptable salt and preferably excipients such as pharmaceutically acceptable diluents and/or excipients.

These are intended to refer to substances which are physiologically acceptable for converting the active compound into a suitable dosage form after mixing with it.

Frequently used excipients or diluents mentioned are, for example, various sugars or starches, cellulose derivatives, magnesium carbonate, magnesium stearate, talc, gelatin, colloidal silicon dioxide, animal or Vegetable oils, polyethylene glycol, water or other suitable solvents, as well as water-containing buffers, to which glucose or salts can be added to make the solution isotonic. Additionally, surfactants, colorants and Frey z-1 stabilizers, as well as preservatives, can be used as further additives in the preparation of the medicament of the invention.

The proportion of active compounds is from 10 to 90% by weight, preferably from 25 to 90% by weight.
It is 75% by weight.

The daily dosage (i.e., the base form or pharmaceutically acceptable salt form of the molecule) can be from 5 to 500 mts oral depending on the action. The amount that can be administered can be distributed over several dosage units for daily administration. One dosage level, especially for oral administration, can contain up to 500 to 1001 IP of active ingredient, but preferably 5 to 1001 IP.

However, larger or smaller dosage units can also be used and, where appropriate, must be divided or multiplied before administration. Suitably, the dosage unit may be coated or embedded with the particular substance, for example in a suitable polymer, wax, etc., to delay or prolong its release over a relatively long period of time, for oral administration. can be microencapsulated.

Non-enteral administration can be carried out in liquid dosage forms such as sterile water and suspensions for intramuscular or subcutaneous injection.

Such dosage forms are prepared by dissolving or suspending an amount of the active compound in a suitable physiologically acceptable diluent, such as an aqueous or oily vehicle, and ensuring that the solution or suspension is sterile and, as appropriate, It is prepared from moth using suitable stabilizers, emulsifiers and/or preservatives.

Pharmaceutical formulations are manufactured using common conventional methods.

Suitable active compounds for the preparation according to the invention are typical compounds which show very high activity in tests of antidepressant activity in humans and at the same time very low or no activity in tests of psychostimulant activity, i.e. Nidoran-3. , 4-diphenylpi to lysine, trans-4-(4-methylphenyl)-3-phenylpi to lysine, trans-4-(4-
methoxyfer)-3-7, cis-4-(4-chlorophenyl)-3-phenylhyboridine and trans-3-phenyl-4-(4-)lifluoromethylphenyl)-pia lysine, and pharmaceutically acceptable salts thereof.

Furthermore, the present invention provides the formula i: 薯 [Wherein, X and YF! , same or different and halo ν/, C1-4-alkyl Q 5% C6-cycloalkyl, phenyl-(01S-C5)-alkyl, trifluoromethyl, trichloromethyl, hydroxyl,
cI Figure 4-Alkoxy, halo (C1<a)-alkoxy, phenyloxy, phenyl-(, C1-C3)
-alkoxy, acyloxy with up to 4 carbon atoms, nitro, N, N-dialkylamino, morpholino or C14-alkylsulfonyl with 1 to 4 carbon atoms in each alkyl group, or the group X and Y
one of the substituents X and Y is hydrogen and n is 1.2 or 3] or physiologically acceptable salts of these compounds, provided that one of the substituents X and Y is Q 1-C4-Alkoxy except for compounds in which the other is hydrogen and n is 2.

Compounds exist in cis or trans form.

Formula (2) also includes racemates and enantiomers.

When n represents 2 or 3, the particular nuclear substituents are the same or different.

Alkyl and alkoxy groups are straight or branched.

The present invention further provides the formula (1): [wherein X, Y and n are defined in formula I]
3,4-diphenylpiboritone is reduced and optionally converted into a physiologically acceptable salt.

The compound of formula (1) is reduced using a reducing agent. Here, a reducing agent is used when it is used under appropriate conditions to reduce an amide function to an amine function without reducing the aromatic ring, and at the same time isomerizes the cis stereochemistry to the trans form. Any reagent that does not cause

That is, a composite hydride of lithium and aluminum (IahQFi) used in ethyl ether at -10°C to reflux temperature.
3) gives lysine to cis-type Pi from lydon to cis-type pi.

LiAAH,1 in dioxane at reflux temperature can be used for the reduction of trans-bicolydone to trans-bicolysine. A solution of diborane in TFIF allows the reduction of piperidone in the trans- or trans form to bihe IJ dine of the same stereochemistry at temperatures between 0°C and reflux.

It is also possible to subsequently introduce the groups X and Y into the 3,4-','phenylpiperidine derivative.

Compounds of formula
- obtained from nitrile ester derivatives (European Patent Application Publication No. 0.203,308 or U.S. Patent Application No. 847.2)
(See No. 55).

The following supplementary information is a report on pharmacological activity testing of the products of formula I or 1a and examples of the preparation of compounds of formula (1) of the present invention, and is intended to provide a better understanding of the present invention.

However, this report and examples illustrate the subject matter of the invention in its own right and do not limit the invention.

The pharmacological test was performed on male rats (Wist) weighing 170-220f.
ar strain) and male mice (NM Shakuko strain) weighing 18 to 23F.

All studies were conducted in a blinded manner (i.e., at the time of conducting the study, the researchers were not informed which test animals received which active substance and at what dose).

Ten animals were used per group unless otherwise specified.

All tests were conducted at constant laboratory temperature (22±1°C).

The test substance was suspended in a suspension of 1y of gum arabic in 2Q of water.

The injection volume was 0.5 m/[Q2 body weight for rats and 0.25 m/20 f body weight for mice.

Acute toxicity was determined by intraperitoneal administration to groups of five mice each. For each dose, the number of surviving animals was determined immediately or 24 hours later. For all products of the invention, the lethal dose was not below 64 Wyi/Kf, but in most cases above 256 tpqI/Kt (the highest dose in the range used).

The antidepressant activity of the compound was significant in anti-reserpine, anti-apomorphine and anti-oxotremorine activity in mice and in the effects of yohimbine toxicity in mice. In these experiments, the first dose was determined to provide statistical confidence. For all compounds of the invention, the first active dose is 0.5η, 9 to 1
6tq/Ky (abdominal, intramembranous or oral).

A number of directional tests directed to the antidepressant effects of test substances in humans include the Nileserpine test (mouse) - Antagonism of the effects of apomorphine and oxotremorine in mice - Yohimbine hypersensitivity (mice) - Sedative behavior and head Subjected to tremor spasm test (mouse). If the test substance showed interesting effects after intraperitoneal administration, it was also investigated after oral administration.

Anti-reserpine activity At 0 hours, reserpine was administered intraperitoneally to mice (2.5 r
q/Kq).

After 4 hours, when hypothermia symptoms are sufficiently strong (30-33°C), the various compounds to be studied are administered intraperitoneally or orally. Rectal temperature is measured every 30 minutes over a 2 hour period using a thermocouple probe inserted at a constant depth. The rectal temperatures of test animals administered with various compounds of the invention are compared with those of a control group given distilled water in the same manner as the test compound.

Motor paralysis (lack of movement) and blepharoptosis (Rubin
(1957), the degree of eyelid opening from 0 to 4) was set to 2.
Similar evaluations are made every 30 minutes over time.

Products with antidepressant action counteract the hypothermia induced by reserpine. Nomicents that suppressed hypothermia are calculated for each dose of compound administered.

Anti-apomorphine activity 0 hours After correcting rectal temperature, mice (6 per group) were placed in individual cages (11 x 3.5 x 4 cm) for observation.
to be introduced. Thirty minutes after intraperitoneal or oral administration of the test substance, apomorphine is administered subcutaneously at a dose of 16η/4+. Rectal temperature was measured 30 minutes after apomorphine administration. Control animals receive distilled water instead of the test compound. Hypothermia observed in these control animals treated with apomorphine 16M9/odor averaged 33°C. Percent inhibition of hypothermia is calculated for each compound dose.

After correcting the anti-oxinotremorine activity M-water temperature, mice (6 per group) are administered intraperitoneally with distilled water or the various test compounds.

Thirty minutes later, occhintremoli/is administered intraperitoneally at a dose of 0.5 Hi/team.

The mice were then observed, with tremors rated from 0 to 3 depending on intensity, and motor paralysis measured every 10 minutes over a 30 minute period.

Furthermore, the appearance of peripheral symptoms (lacrimation, gastrointestinal emptiness) is observed for 2 hours. Rectal temperature is measured every 930 minutes for 2 hours after administration of ochinetremorine.

Products with antidepressant action counteract the hypothermia induced by ochinetremorine.

The cent inhibition of hypothermia is calculated for each dose of compound.

Effect on Yohimbine Toxicity At time 0, mice are administered intraperitoneally with distilled water or the various test compounds.

Then after 30 minutes, they were given 25a of yohimbine hydrochloride.
Subcutaneous doses of P/Kf are administered subcutaneously.

Mortality is checked every 91 hours for 4 hours and recorded 24 hours later.

Products with antidepressant effects promote enhanced yohimbine toxicity.

Foraolt et al. (rArch, Engineering, Pharm
ac-ridyn, Ther, J229, 327-336
(1977), the hopeless behavior test compound is administered intraperitoneally 30 minutes before the start of the test, and the test animals are individually housed before the forced swim test.

The length of non-movement time is measured 2 to 6 minutes after introducing the test animal into the water and is expressed in seconds.

Sj, eru, etc. ([psychopharmaco
1og7Jdan5. 367-570 (1985) The test substance is administered intraperitoneally 30 minutes before the test and the test animals are isolated (1 for each dose).
0).

Non-exercise time in seconds is evaluated over a 6-minute test period. Examine this reduction in non-exercise time.

○rtmann etc. (jDruq Developmc+
nt FteaarchJ.

Raw, 595-606. L-5 according to the description of 1984)
- Enhancement of the action of hydroxytryptophan (L-5+ (TP))
(head spasms). The test substance was administered to the test animals (
(10 animals per dose) intraperitoneally. Convulsive head movements and tremors were assessed for 1 minute every 10 minutes for 1 hour continuously. Desimibramine (dssimi-pramine) and inglupine (1ndalTJine) serve as control (comparison) compounds. The antidepressant effect is pronounced through increased convulsive head movements and tremors.

The test substances were subjected to several directional tests for psychostimulant activity. In these tests, compounds were tested to see if they lack this type of activity or are only active at significantly higher doses in directional tests of antidepressant activity.

This test measures the amount of exercise (actimetry).
try ) (-qus) - Study of open-mouth behavior (rat) - Regarding interaction with barbiturate.

Momentum measurement (actimetry w Actimetr7
) photoceil actime
ter.

Boisaier ana Simon, [Arch
, ■nt, PharmacOdyn.

1965, 1! 212-221) to measure locomotor activity.

Mice (10 or multiples of 10 per group) are introduced into the motor needle immediately after intraperitoneal administration of the test compound. Locomotor activity is then measured at 60 minutes.

The counter is read after 30 minutes, then reset to 0 and read every 10 minutes for 50 consecutive minutes.

The locomotor activity of animals treated with various compounds is compared to that of a control group fed distilled water.

Products with psychostimulant activity cause an increase in the amount of jTυ.

Investigation of open-mouth behavior in rats Immediately after intraperitoneal or oral administration of the test compound.

Test animals (6 rats per group) were placed in a 20x10x10
The cells are introduced into individual transparent plastic cages with stainless steel covers with holes measuring 1 cm in diameter and 1 cm in diameter. Stqreo-typical behavior
vement) (mouthing, sucking, licking or chewing) every 10 minutes until they disappear in all animals.
harmacol, Parish, 1972.3.2
Evaluation is made on a scale of 0 to 30 according to the method described in 35 to 238).

n) Antagonist test animals (6 mice per group) for IJ umbarbital-induced sleep were treated with 20 x 10 x 10 cr.
A hypnotic dose of sodium parbital (180 μ/Kf i.p.) was introduced into individual transparent plastic cages.
The test compound or distilled water is administered intraperitoneally or orally 60 minutes before the administration of the test compound or distilled water.

The times of suppression and reinstatement of the righting reflex are recorded for each animal. The presence of psychostimulant activity is pronounced in the neutralization of sodium parbital-induced sleep.

Subjecting certain substances to analgesic testing.

Hot plate test: yacoh and Blozovsk
i (“Arch.

nt, pharmacodyn, J 133.29
6-209. The reaction time on the hot plate expressed in seconds for licking and jumping movements is evaluated according to the criteria for front paw clawing and animal jumping as described in (1961).

Two responses are observed in the same untrained animal, with a maximum reaction time (upper limit) of 240 seconds. The temperature of the plate is maintained at 56.6°C.

Morphine subcutaneously as a positive control group and other substances C
rnq/9) is administered intraperitoneally 30 minutes before the test.

A positive reaction is evident by an increase in reaction time.

If the damage avoidance effect of the test substance is neutralized by naroquine, it can be determined that this substance actually has an analgesic effect.

Results Antidepressant activity: A first dose was specified that would provide statistical confidence. This first active dose for all compounds of formula
It was 9 to 6 tq/.

Table 1 shows the antidepressant and psychostimulant activities of some of the compounds of formula i or 1a tested.

If there are several values for a compound, the lowest value is for intraperitoneal administration.

The values in columns 2-5 are from the book on the antidepressant activity of the compound, and the values in columns 6-7 are on the psychostimulant activity. After administration of the test compound, locomotor activity can be expressed as whether it decreases (\), remains unchanged (-), or increases (,/). Lightning homozygous behavior was not observed when decreased locomotor activity was observed. The dose w9/9 that causes a significant increase in locomotor activity is shown in column 6. Doses that cause an increase in locomotor activity or psychopathic behavior are significantly higher than doses that give a positive response in antidepressant activity tests.

Table 1a summarizes the activities of the comparative compounds and the compound of Example 3.

*Tail suspension test, test = 4■, /9 positive from intraperitoneal*
*For all compounds of formula I or la that tested positive from the 9 abdominal cavity in -811111,/, they did not increase locomotor activity (256 cape 5/
It was also found that antidepressant activity was enhanced only at doses significantly higher than the effective dose in the directional test.

The results of the sedative behavior and head spasm test and the analgesic test using trans-3,4-diphenylpyrr-lysine (ryr) are shown separately.

Calming behavior test 8 by porsoxt From 9 to rrq/, r:rprTha non-movement time (D
It shows a significant fxWt decrease, and the effect becomes larger at '+6rq,/Kp.

At the latter dose, DPPT has no stimulatory effect on mice.

The activities of nomifensine, desipramine and imipramine at approximately the same dosage are shown in Table 2 for comparison.

Table 2 Mouse “sedation behavior” DPPT 16 10 94±17p
<0.001, +7% control group 20 1
97±9 Nomifuensin 4 10 120±23p
<0.001 39% control group 20 201
±9 Desibramine 8 20 105±16 p
(From the 0,001489g mouse tail suspension test 2tq,/~, DPPT shows a significant decrease in non-exercise time. For comparison, the results when imibramine and nomifensine are used are shown in Table 3.

Table 5 Mouse suspension test dose control group 77±9 DPPT 1 58±13
25%2 38± 7p<0.01 51%4
16± 2p<o, ool 79X16
12 Sat 3p<0.001 84% control group
102± 8 Imipramine 1 70 17
31%2 59± 8p<α01 42%4
53±11p〈α01 48%8 48±10
p<0.01 58%16 28± 7p<
O,0C1173% control group 91± 6 Nomifensine 0.06 59 q
559'i; 0.25 1± 6p
(0,0155%1 31± 6p<0.rJl
66%4 18± 5p<0.001
aO%L-5HTP-enhanced DPPT causes an increase in L-5HTP-induced convulsive-like head behavior (head twitching) in mice. The action is 81q
/ V4 is obvious and reliable. Tremor increases as well (Table 4).

Table 4 Mouse L-5-hydroxytryptophan enriched D
PPT 8 4.7±0.6p<0.01 1
5±0.4 Control group 2.1 0.30 Desipramine 4 580 0.4p (α01 0.5
±0.2 Control group 2.1 α20 Indalpine 1 4.1±0.7p<0.01
2.0 Practitioner Q, 7 Analgesic Test: Hot Plate DPPT is tested in mice subjected to heat-pain stimulation 2
It has activity against two reactions. The effect is 161M1/K
It has statistical reliability at f. The results using desicheramine, indalpine and morphine are also shown in Table 5 for comparison.

The damage-avoiding effect of DPPT is enhanced by Narokine (antagonist).
Attach it. This latter result indicates a true analgesic effect of the test substance (Table 5a).

Table 5 Mouse hot plate test dose control group 5.1±C1,59Q±7 vs. vocal group Vero±0.7 96±9Dp
Pτs 7. []±0.9 1113±
1016 9.9±2.0 135±14p(
0,05321i0±1.7p (0,01193shi17
p<0.001 control group 5.5±04
86±10 morphi, ne 2 a1±0
．． 6p (0,01158±17P<0.01 Table 5a
Mouse hot plate test, interaction dose treatment with Narokine [η7f:q'J cavity licking motion 51.
≧ and motion control group 5.3±0.3
84±10 Naloxone 0.5 5.5±0.3
65±6 control j$ 5.9±0.
5 78±6 Naloxone Q, 5 5.2 0.3 67±5 As a non-limiting example, exemplary preparation methods and physicochemical property data for the new compounds are described below.

Example 1 Preparation of cis-4-(4-methoxyfer)-3-phenylpi-lysine 1 cis-4-(4-methoxyfer)-3-phenyl-2
Lidone 211 (α071 mol) was added to a flask containing 1 g (1026 mol) of lithium aluminum hydride and 60 cm of anhydrous ether in portions over 15 minutes, and the mixture was kept at −1 DC under nitrogen with stirring. did.

The reaction mixture was allowed to stand at room temperature for 1 hour and then diluted with water at 15C.
Hydrolyzed using 0 efn3. The ether was removed by evaporation and the residue was dissolved in methylene chloride (4X 3 (1,
y3) and dried over anhydrous sodium sulfate.

After evaporation, a viscous mixture containing about 80 units of piperidine was obtained quantitatively. This was purified by chromatography on silica.

Flash chromatography: silica 230 in column
~400 Metsis A8TM, 25 cm and 4 cutting diameter,
Flow rate 15533/min, eluent ethyl acetate/methanol 4
0/60Rf-α27 After removing the solvent by evaporation, 1.42 g (74%) of a white hygroscopic compound corresponding to a narrow cis-1-racemate was obtained. Melting point -69~70C0 M point of hydrochloride=203~2
04°C (absolute ethanol).

Elemental analysis: cBIH21N.

Actual measurement value 79.767.935.136.65 engineering R (
KBr) (base): b N-H3330cM-'I
weak.

Mass, (/%? ctor (base): (70ev), m/
e (specific intensity): 267 (,77; M"), 247 (1
7), 176 (28 people 169 (38), 134 (28)
, 133(47).

104 (100), 91 (t?), 77 (21), 57
(32).

NMR80MH2 (base) CDCl3 near, 55~
&95ppm (5H, Ar, composite peak) 6.90-6
．． 55 ppm (4H, Ar, composite peak) 570
ppm (3H, day, methoxy) 150-2-
70 ppz (6H, @broad composite peak) 2.40-1
．． 45ppe (3H, ME single rent 1.82pp
m).

N! ,! F, 350 MHz (hydrochloride) CDC4;
:1α10~9.80 ppm (2H, NH2) composite peak) 7.22~7.10 pnm (3H, Ar, composite peak) 6.95~6.86 ppm (2H, Ar
, composite peak) 6.82 ppm (2H,A
r, d,, :r ortho-meta-a4Hz) 6.68 ppm (2H,A!-,a,
,'::Orthometal=a4Hz) 180-3.70 ppm (4H,!, 75ppm
3.63-540prm (5H, composite peak) 16
3-2.47 ppm (IH, composite peak) 2.6
3-2.24 ppm (IH, g combined peak) Example
2 trans-4-(4-methoxyfer)-3-phenylpyR lysine hydrochloride 2:1
,07t mol)% lithium aluminum hydride 0.65
．． '9 (17 moles of CLO) and anhydrous dioxane 30
cm3 was charged into a 1f) OcFn' volume flask under stirring under a nitrogen atmosphere.

The mixture was refluxed for 1 hour and then hydrolyzed with 1°-5 of water at 0°C to 5°C.

The solid residue obtained after evaporating the solvent was extracted with methylene chloride (6X15m5) and the organic layer was dried over anhydrous sodium sulfate.

After filtration, hydrogen chloride gas was passed through the organic layer for 5 minutes.

After evaporation, a yellow, brittle solid was obtained, which was recrystallized from 15 cfR5 of a 60/40 mixture of ether and absolute ethanol.

After filtration, washing with anhydrous ether and drying, a hygroscopic crystalline product 1.36 JF (62%) corresponding to the pure trans racemic 2 hydrochloride was obtained. Melting point = 218-220
℃.

Elemental analysis: Calculated value assuming Cl8H21NO・HC206 mol 6a70 7.38 4.45 11 Actual value
6a597.344.4811.4DIR(xBr)
(Hydrochloride): Broad ammonium band, center 27503
-' Near strong band 2920cfn-' (Sea CH2
-).

Mass (hydrochloride): 70 eVs m/e
(Specific intensity): 267 (78; Mho), 224 (5
), 210(7).

176(31), 167(5), 165(B), 159
(5), 152 (5), 147 (8), 134 (24
), 133 (44), 121 (14), 104 (100
), 91(12), 7B(7), 77(8), 57(2
2), 56(15).

NMRS 50 MHz (hydrochloride) CDCl2:
10 ~ 2.85 ppmz (2H, IH2, composite peak) 7.20 ~ 6.90 ppm (7J Ar, composite peak) 6.68 ppm (2H, hr, d
,,! Orthometer a4MHz) 3.80-3.54 ppm (5H, 3,68pp
Composite peak with methoxy singlet at to) 554~440ppm (IH, composite peak) 524~
&O4ppm (2I composite peak) 500 ~ 2.85
ppm (1H, composite peak) 2.52~'1.56
ppm (1H, composite peak) 2.22-2.02 p
pm (IH, @ combined peak).

Example 3 Preparation of trans-3-phenyl-4-(4-trifluoromethylphenyl)-pyR-lysine hydrochloride 3 trans-3-phenyl-4-(4-)trifluoromethylphenyl)-2-piperidone 5I (α015 mol),
Lithium aluminum hydride 1.5I (α039 solu)
and 60 an' of anhydrous dioxane were introduced under a nitrogen atmosphere with stirring.

The mixture was refluxed for 45 minutes and then hydrolyzed with 250ml of water at 0-5°C.

The solid residue obtained after evaporating the solvent was extracted with methylene chloride and the organic layer was dried over anhydrous sodium sulfate. After filtering the organic layer to remove the solvent, 4.7 g (98%) of a yellow oil was obtained, which was chromatographed on 230-400 mesh ASTM silica (eluent: 6
0/40 ethyl acetate/MeOH).

Oily product A3l corresponding to pure trans racemate
1 (69%) was obtained from this product. After partially dissolving this oil in a small amount of anhydrous ether, HCt gas was bubbled through the mixture.

After evaporating off the solvent, the pure trans-hydrochloride of lysine 3 was obtained (67%) in the form of a friable foam.

Elemental analysis values: Cl8H+, 9CtF3Nα44 (8-distilled value 61.81 5.72 4.0
0 1 α12 actual value 61.816.153.89
9.90 mass is ctor: (70eV); rn/
e (specific intensity): 306 (8), 305 (4!, 7
; li"o-HCt), 304 (a6 regret), 256 (
5), 167(12), 149(32,7), 157(
12,4), 133(9), 132(14), 104(
30), 97(13), 95(13,5), 91(1
3), 85 (14), 81 (37), 57 (700)
.

NMR13C: cncz5 base 54.585 (L234a9235.5047.0
3 Salt Salt 49.77 45.48 46.84 3(
15744,60 Example 4 trans-3-phenyl-4-(4-trifluoromethylphenyl)-pi is lysine maleate 4! ! 1""L' 60 cms medium mashimaleic acid 559
Pure trans-3-7enyl 4 of Example 3 ([10047 mol) dissolved in anhydrous ether 40 cyn'
-(4-trifluoromethylphenyl)-piperidine base 1.1. Add dropwise to F (0,0036 mol),
The mixture was stirred overnight. The formed precipitate was filtered. The 1,P (66%) obtained here was recrystallized from a mixture of ethyl acetate/ether to obtain 119.19 (51%) of the pure maleate salt 4 in the form of white crystals. Melting point -146
~147℃.

Elemental analysis value: C22H2213NO4 calculated value 62.
70 5.26 13.52 532 actual measurement 62.
60 5.27 15 27 3L25 Example 5 Preparation of trans-4-(4-chloro-trifluoromethylphenyl)-3-phenylpiperidine hydrochloride 5 Trans-4-(4-
Chloro-3-trifluoromethylphenyl)-3-phenyl-2-pi was dissolved in 15 ml of a grained, 772 M solution in THF at 0° C. under nitrogen with stirring Lydon 1 (α0 169 mol).
'((103 mol) K was added over 35 minutes. The resulting colored solution was then refluxed for 2 hours. 6N hydrochloric acid 10-3 was added at room temperature, the THP was evaporated off and the residue was dissolved in methylene chloride. Recovered.

Sodium hydroxide solution was added to 12 tones and the mixture was washed neutral and dried over anhydrous sodium sulfate.

After evaporation, a viscous oil essentially containing the desired pyrrolidine 5.2. F (90%) was obtained. 23
After purification by flash chromatography on 0-400 mesh ASTM silica (60/40 ethyl acetate/methanol), 4.4 g of piperidine base were obtained, which was dissolved in 60 m5 of anhydrous ether to give the salified salt. Dissolved.

4.34 g (58%) of a friable foam corresponding to pure trans-4-(4-chloro-3-trifluoromethylphenyl)-3-phenylupid lysine 5 was obtained.

Elemental analysis value: Calculated value based on cl, 3a1Bcz2y3N09 moles 55.10 5.07 1a07 14.
52 556 actual measurement value 55.255.2N 17.8
314.79540 mass spectrum: (70eV), m
/e (specific intensity): 342.0 (2,8), 340.9
(13,4), 34o,o(1α1), 339.0(4
0,6), 33aO (6,1), 17aO (11,2)
, 1350 (1CL7), q32.0 (16,0), t
04.1 (47,2), 91.0 (17,3), 77.
0 (1α5), 57.1 (93,6), 56.1 (53
, 1), 44.1 (100).

NMR"C: CDC23 C'2 05 C4C5C6 δ 49.4845.43 46.36 3 [1204
4,39NMR550MHz: 9,90 ppm (2H, MHz, MHz
) 7, 40-6.90 ppm (8H2Ar, composite peak) 3.74 p]) 口CH6e* ”) 3
．． 64pprn(H2eIrn・) 3.53 1)riτ (Moa+”) 3.19
ppm (H6a+ H2B, m,)1
05 ppm CH4a l”°)2.
60-2.42ppm (Hse, m,)2.11
ppm (Hse, m,) Example 6 Preparation of trans-4-(4-chloro-3-trifluoromethylphenyl)-3-phenylhyhelicine maleate 6 Maleic acid 6 was prepared in the same manner as in Example 4. Obtained from pure trans-4-(4-chloro-3-trifluoromethylphenyl)-3-phenylpyharidine base, which was recrystallized from an 80/20 ethyl acetate/methanol mixture into crystals. Melting point = 185-186°C.

Elemental analysis value: C22H2jCff3NO4CHCL
F N calculated value 57.95 4
．． 61 7.79 12.51 3.07 Actual value 5a
05 4.64 7.73 12.56 3. O.

Mass is vector: (70ev), m/e C specific intensity) =
342.1 (2,2), 341.0 (12,5; M
"O), 340 (a9), 339.1 (36,7; M
ho), 338.0 (3,9), 266.1 (11,5
), 24 aO(6,6), 1951(9,7), 18
1.0 (6,1), 180.0 (37,4), 179.
0(21,8), 17aO(21,7), 165. IC
11,9), 1351 (1 (L7), 132.0 (254), 131.0 (7a6), 119.0 (6,2),
11 ao(64,2), 117.1(47), 1[
1 (3,1), 115.1 (19,8), 105.1 (
9,3), 104.1 (49,9), 103.0 (IC
l3), 102.0 (6,6), 91.0 (27,4)
, 89.9 (17,6), 89.0 (12,4)
, 7a0(a6), 77.0(1,1), 7aO(3
, 3), 44.1 (100).

Example 7) 97-4-(4-mesyloxyphenyl)-3-7
Preparation of 22rubiveridine hydrochloride 7 81: ), yinsu 4-(4-hydroxyphenyl)-3-phenylpiperidine hydrobromide v! 4 unmade brine methylene chloride 10
boron tribromide 2α8F (0083 mol, 9
m') was added over 1 hour and 20 minutes to a solution of 92 g (0,030 mol) of 2 in anhydrous methylene chloride 250α3 under nitrogen at −35° C. with stirring.

The mixture was left at room temperature for 4 hours and then the product was subjected to metalysis (anhydrous methanol 230#) at -35°C.

The temperature was then increased again and a high velocity stream of nitrogen was passed through the reaction mixture to drive off excess hydrogen bromide.

After stirring for 4 hours at room temperature, the solution was evaporated under vacuum (temperature ≦30 °C). By this method, beige solid a! (
84%) was obtained and recrystallized from 95 liters of ethanol.

Product weight: 8! q0 yield 79cm. Melting point = 263-26
4℃.

Elemental analysis value: C17H20ErNO Calculated value 61.0B,'1.03 4.19 23
．． 90 Actual value 6Q, 92 6.08 4.06 23
．． 84 Engineering R (KBr): y N-H3260oy+-
”, medium intensity.

Mass is vector: (7osv), r=/e (specific intensity)
:253.1(100; Mho), 196(ii
), 164 (10), 162 (31), 133 (40)
, 132(15), 120(19), 107(13),
105 (15), 104 (92), 103 (11), 9
1 (15), 82 (23), 81 (11), 80 (25
), 79(11), 77(13), 57(36), 56
(23).

Step 2: N-benzyloxycarbonyl-trans-4
Preparation of -(4-hydroxyphenyl)-3-phenylpilysine) trans-4-(4-hydroxyphenyl)-3-phenylpiperidine hydrobromide 6.5 g (0019 mol)
and sodium 4 borate 7.9, p (co69 mol)
The mixture was stirred in 100 cm' of sewage at room temperature.

Indyl chloroformate 51 (0029
mol) was added dropwise while the temperature of the reaction mixture was kept at 9 using 2N aqueous sodium hydroxide solution.

The mixture was stirred for 45 minutes at room temperature and neutralized with dilute hydrochloric acid.

The mixture was extracted with methylene chloride (5 x 80 iy') and the organic layer was washed with water and dried over anhydrous sodium sulfate.

After evaporation, 8 g of a reddish-yellow oil was obtained which was recrystallized from ether to give 5.81 g of a white crystalline product, which corresponded to the desired product and was quantified. obtained. Yield: 77 cm.

Step 83: N-benzyloxycarbonyl-trans-4-(4-mesyloxyphenyl)-3-phenylpiA I) Preparation of zine Mesyl chloride 1
．． 2.51 ([1 (N mol)) of N-benzyloxycarbonyl-trans-4-(4-hydroxyphenyl)-3-phenylpiperidine 2.9 ([1005 mol)] in anhydrous pyridine 121 M5 at O<0>C under nitrogen. was added dropwise.

The reaction mixture was stirred at this temperature for 2 hours and then placed in the refrigerator for 24 hours. Next, mix the mixture with 50 y of ice and 13 ml of concentrated hydrochloric acid.
Pour it into a beaker containing fn3.

The mixture was extracted with methylene chloride (4 x 80 cIn5) and
The organic layer was washed with anhydrous sulfuric acid and dried over IJum until neutral (washed 2x3 by++3).

After evaporation, 2.15 g (89%) of a yellowish foam were obtained.

The isolated product was purified by flash chromatography (230-240 meshes of silica gel, eluent: hexane/ethyl acetate 60/40).

The desired product 1.7y was obtained in this way. Yield: 71 inches.

Step 4 Preparation of Nia In an autoclave, N-benzyloxycarbonyl-trans-4-(4-mesyloxyphenyl)-5-phenylpi is lysine 2.3/(0005 mol) + 104 Pa
/chacol α4y and glacial acetic acid 40ctn5 10
Stirred for 6 hours at room temperature under bar hydrogen pressure.

After filtration and evaporation, the oil obtained in this way was taken up in 120 cm' of methylene chloride, the organic layer was washed with water until neutral and finally dried over anhydrous sodium sulfate.

After evaporation, an orange oil was obtained quantitatively, from which the hydrochloride salt was prepared.

The hydrochloride salt obtained from this was purified by flash chromatography (250-240 mesh silica gel column, eluent: ethyl acetate/methanol 60/40 then methanol). White solid CL9. which cannot be recrystallized and corresponds to the desired product 7. F was obtained by this method. Yield 50%
.

Mass: (hydrochloride) (70 V); m/s (specific intensity): 331 (5; M+0), 104 (10), 9
1 (6), 74 (66), 60 (38), 59 (100
).

NMR (“C): CDCl2; ppm: C2C5C
d c5 C6C5δ 49.77 45.
82 46.75 3CL59 44.65 37.5
2 Example 8 Preparation of trans-3-(4-chlorophenyl)-4-phenylpiboridine 8 6-(4-chlorophenyl)-4-phenyl-2-hibalidone dissolved in anhydrous dioxane 20-5 1.21
(α004 mol) and lithium aluminum ahydride α
41! (101 mol) was placed in a flask and stirred under a nitrogen atmosphere. The reaction mixture was slowly heated to the reflux temperature of dioxane over 1 hour and maintained for 1 hour and 15 minutes. During hydrolysis, the reaction mixture was It was cooled to 0.degree. C. and 20.degree.

After filtration and solvent evaporation, the product 1.1719 containing trans-piperidine 8 and about 20% impurities was obtained. The mixture was purified by flash chromatography (column containing silica gel 60 (230-400 mesh ASTM), ethyl acetate/methanol: 60/40, nitrogen pressure: α2 bar).

This results in trans-piperidine 8 with a melting point of 55-58°C.
1.05g of was obtained.

The hydrochloride salt obtained in the form of a brittle foam could not be recrystallized.

Engineering R (KBr): v N-H3220cWI-',
Weak peak.

Mass spectrum: (70eV), rn/e (specific intensity)
:275 (36t"Q), 271 (100, Mho),
273 (i6), 179 (22), 178 (35),
166' (16), 146 (30), 140 (20),
138 (53), 115 (17), 104 (21), 1
03 (23), 91 (29), 86 (1B), 84 (2
7), 77 (23).

Example 9 Cis-4-(4-methylphenyl)-3-phenylpi is a preparation of lysine 9. Cis-4-(4-methylphenyl)-3-phenylpi is a mixture of 8 g of lydone and lithium hydride in anhydrous ether 1400 + 1' under nitrogen. Aluminum 4.5 Ji' (Qj 18 mol) was added little by little over 1.5 minutes with stirring into a flask, and the reaction was allowed to proceed at room temperature for 1 hour. After treatment, pure cis-type pi with a melting point of 55-57°C has lysine 9 of 5.25
11<69ch) was obtained.

Elemental analysis value: 018H21N CHN Calculated value 86.01 &41 5.57 Actual value 85
．． 71 &36 5.50 engineering R (KBr): v
N-H2320tM-', weak peak.

Mass spectrum' (70eV), m/e (specific intensity)
:251 (10Q, Mho), 208 (12), 17B
(11), 160(30), 159(11), 133(
27), 132 (27), 11B (16), 117 (1
8), 115 (12), 105 (20), 104 (
68), 103(12), 91(18), 77(12)
.

57(36), 56(27).

The hydrochloride salt of cis-4-(4-methylphenyl)-3-7dynylpyharidine was prepared by conventional methods. This was recrystallized from a methylene chloride/hexane mixture. Melting point = 22
7-230℃.

Example 10 Preparation of trans-4-(4-methylphenyl)-3-phenylpi-lysine 10 The appropriate trans-piperidone 7,5 I! was reduced using conventional methods. As a result, trans-type lysine 10 was quantitatively obtained. Recrystallized from a ternary mixture of ether/hexane/methylene chloride (60/30/10), melting point 9.
Crystals of pure trans-lysine were obtained at 0-93°C.

Elemental analysis value: Cl8H21N Calculated value (0.22 mol of water) 84.68 &4
5 5.48 Actual value 84.68 a4
9 5.43 Engineering R (KBr): y N-H3340c
fn-', the medium intensity mass is Chtorni (70eV
), rn/e (specific intensity); 251 (11:10.M
ho), 208(13), 194(8), 179(1
1), 17B (13), 160 (32), 1s9 (11
).

135 (26), 132 (1a), 131 (1o), 1
18C13), 117(10), 115(11), 10
5 (18), 104 (63), 91 (4), 77 (8)
, 57(40), 56(29).

The N-benzoyl derivative of trans-piperidine 10 was prepared in a conventional manner and dissolved in absolute ethanol/ether (60/40
) to obtain crystals with a melting point of 13Z5 to 13a5°C.

The trans-type P prepared by the conventional method was obtained by recrystallizing the hydrochloride of lysine 10 from methylene chloride to obtain crystals with a melting point of 253-254°C.

Example 11 Preparation of trans-4-(4-acetoxyphenyl)-3-phenylpiperidine hydrochloride 11 1.) Acetyl chloride 5.5z3 (1077 yl) was dissolved in anhydrous pyridine 50c! under nitrogen at 7°C. N-benzyloxycarbonyl-trans-4-(4-hydrodiphenyl)-3 dissolved in n5
-Phenylpiperidine (compound described in Example 7) 1
CL8jl ((1027 mol) was added with stirring. The mixture was stirred for 7 minutes at 7°C and then for 48 hours at room temperature. The reaction mixture was poured onto ice 250I and extracted with methylene chloride (4x100an5). The organic layer was washed with dilute hydrochloric acid until acidic and with water until neutral, then dried over anhydrous sodium sulfate. After filtration and evaporation, a brown foam was obtained quantitatively. This was then dissolved in a minimum amount of ethyl acetate and the solution thus obtained was filtered over 230-400 mesh ASTM silica gel. The solvent was evaporated and the resulting residue was purified with 714 crystals from 95% ethanol. and 19-benzyloxycarbonyl-trans-4-(4-acetoxyphenyl)-
3-Phenylpiperidine Z6y (63%) was obtained in the form of white crystals. Melting point: 120°C.

2)) Above compound 3F ([1007 mol), glacial acetic acid 50
oy+' and palladium/charcoal (10%Pd/
C) cLsy was placed in a 250 cm5 volume autoclave and the mixture was stirred at a hydrogen pressure of 1[] bar for 4 hours.
Hydrogenated for hours at room temperature. After filtering and evaporating the solvent,
An oil was obtained and dissolved in methylene chloride.

After passing hydrogen chloride gas and evaporating the solvent, a soft foam is obtained which is recrystallized from an ethanol/ether mixture with a melting point of 198°C (the change in appearance is around 193°C).
1.9&(82%) of hydrochloride 11 was obtained.

Elemental analysis value: 43 moles of water per c19H22cmo2) 67.20 6.78
4.12 1α44 actual value 67.186.79
'5.981160 Engineering R (KBr): v C=017
5[]m-', strong peak, N+2640-2820c
m-1, strong peak.

Mass: (70eV), rnle (specific intensity)
:269.1 (1111Li), 294.9 (73,8
, Mho ), 253.0 (3,4), 204.0 (2
1,4), 196.0(9,9), 16s,.

(3,1), 162.0 (9,5), 135.0 (6,
6), 1350 (2%), 132.0 (1aO), 1
21.0 (3,5), 119.9 (21,2), 115
．． 0(3,2), 107.0(9,3), 105.1(
154), 104.0 (100,0), 103.0 (7
,5),91.0(12,9),7zo(al),57
．． 1(8(lLl), 56.1(33,9).

N'MR (15C): (CDC43): Signal δ p
pmC2C♂ C4C5C6CfiltrationH3 49,6443,7246,503CL57 44.5
521.07 Example 12 Preparation of cis-4-(4-chlorophenyl)-3-phenylpi-lysine 12 15
C. and introduced into a flask containing 1i lithium aluminum hydride (no. 26 moles) in 30.degree. C. of anhydrous ether with stirring over a period of 15 minutes. After the addition was complete, the reaction was allowed to proceed for 30 minutes, and then the mixture was hydrolyzed at -5°C by dropwise addition of 8 an5 liters of water, followed by 5 an inch of methylene chloride.
゜c! R3 was added to adjust - to 7. After evaporating the solvent, the residue was extracted with methylene chloride (4x25an5) and the organic layer was dried over anhydrous sodium sulfate. After filtration, evaporation of the solvent gives a crude product which is recrystallized from an anhydrous ether/hexane (60/40) mixture to give a highly hygroscopic cis product 12 with a melting point of 63-65°C. 1.1 (63%) was obtained. The melting point of the N-benzoyl derivative was 152-153°C.

Elemental analysis value: c24a12ctN.

Water [113 mol) per CHC6N O 76.21 5.92
9.37 570 4.78 Actual measurement value
76.21 5.84 9.22 3.7+ 4.4
2nd Engineering R (KBr): v N-H2320IM-1,
Weak peak (product 12).

Mass is ctor' (7 oav), m/e (specific intensity),
(Product 12): 273.1 (36, M”O),
271.0 (100゜M〇), 237 (19), 18
0(24), 179(18), 178(1B), 133
(22), 132 (25), 115 (12), 105 (
12), 104 (85), 103 (21), 91 (16
), 78 (12), 77 (15), 15 (72), 5
6 (46).

Example 13 Preparation of trans-3-(3,4-dichlorophenyl)-4-phenylpyRlysine maleate 13 in THF2.
20M borane solution g, 14.2 g (α0313 mol)
trans-3-(3,4-dichlorophenyl)- dissolved in anhydrous THF 55cfn3 in QC under nitrogen atmosphere.
Added to 4-phenyl-2-heslydone 61 (001874 moles) over 25 minutes.

The resulting solution was refluxed for 2 hours. After cooling to room temperature, 6N hydrochloric acid 5crR3 was added, THF was distilled off, and the residue was dissolved in 100 an3 dichloromethane.

10 cm3 of sodium hydroxide solution were added and the organic layer was separated, washed with water until neutral and dried over anhydrous sodium sulfate.

After evaporation, the desired pill I) Gin 90% (
Analytical high pressure liquid chromatography, Lartisi1
10 columns, eluent: ethyl acetate/methanol/NH
A viscous oil containing 5.4.9 (94%) of 4Br (60/40/CLO2m) was obtained.

The biR-lysine obtained above was directly converted to maleate.

Maleate salt: Crude piperidine dissolved in 150 cm5 of ether was added with stirring to a solution of 2.73 yg ([10235 mol) of maleic acid] in 200 an' of ether and the mixture was left at room temperature for 1 hour.

After evaporating the ether, the crude maleate salt was recrystallized from absolute ethanol. In this way pure trans-piperidine 3 2-85y (36%) was obtained. Melting point -162~164°C.

Elemental analysis value "21H21Ct2NO4 Calculated value% 59.73 5.01 16.79 53
2 actual measurement (Xchi 59.47 5.06 16.92
530 engineering R (KBr): ν=N” 1615cm-1
, medium strength, ν CCOθ1560efn-1, medium strength II! , 1560. Strong peak, $I CH=
CH (cis) 695c! n-1, strong peak;

Mass vector: (70eV), m/e (specific intensity: 309 (12, 3, Mho-116), 307 (61
, 1, M+0-11 (S), 305 (Mho-116)
, 212(12,5), 202(152), 201(
12,5), 200 (14), 178 (23), 176
(14), 174 (3α5), 172 (43), 1a6
(32,5), 119(10), 117(1[L5),
115 (12), 104 (15), 103 (11), 1
02 (12), 99 (115), 91 (:21.5),
77 (12), 72 (41), 57 (100), 56 (
58).

The pio 17dines described in Examples 1-13 and other corresponding pyRlysines of formula I of the present invention, synthesized by methods analogous to the previous examples, are shown in Table 6 below.

As shown in the text and Table 6 above.

The invention is not limited to further details of the embodiments, methods and applications, but also covers all modifications that occur to those skilled in the art without departing from the scope and description of the invention. It is.

Example 26: Capsules Capsules suitable for oral administration contained the following ingredients and could be prepared in known manner by mixing the active ingredient with auxiliaries and introducing the mixture into gelatin capsules.

DPFT 50ff
l7 milk 11 100++v cornstarch 30
wq Merck 3 ■ Colloidal silicon dioxide 511q Magnesium stearate 29 Example 27
: Capsules Capsules with the following composition were prepared by mixing the active ingredient and auxiliaries and introducing the mixture into gelatin capsules.

Compound of Example 2.3.10 or 12 100■
Microcrystalline Cellulose 10019 Corn Starch 50 Misaki Talc
5 Cape Colloidal Silicon Dioxide
219 Magnesium stearate 3WI patent applicant 2 persons other than Laboratoire Hoechst Société Anonymous

Claims (1)

[Claims] 1) Formula (Ia): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(Ia) [In the formula, X and Y are the same or different and represent hydrogen, halogen, C_1-C_4-alkyl , C_5~C_6-
Cycloalkyl, phenyl-(C_1-C_3)-alkyl, trifluoromethyl, trichloromethyl, hydroxyl, C_1-C_4-alkoxy, halo-(C_1
~C_4)-alkoxy, phenyloxy, phenyl-
(C_1-C_3)-alkoxy, acyloxy with up to 4 carbon atoms, aminonitro, N,N-dialkylamino, morpholino or C_1-C_4-alkylsulfonyl with 1 to 4 carbon atoms in each alkyl group; cis- and/or trans-3,4-diphenylpiperidine derivatives or physiologically acceptable salts of this compound in racemic or enantiomeric form. 2) The antidepressant according to claim 1. 3) 3 as set forth in claim 1 as an antidepressant
, 4-diphenylpiperidine derivatives. 4) trans-4-(4-methylphenyl)-3-phenylpiperidine, trans-4-(4-methoxyfer)-3-phenylpiperidine, trans-3-phenyl-4-(4-trifluoromethylphenyl) -piperidine or cis-4-(4
2. A medicament according to claim 1, comprising -chlorophenyl)-3-phenylpiperidine or a physiologically acceptable salt of one of these compounds. 5) in the form of a racemate or enantiomer of the cis- or trans-3,4-diphenylpiperidine derivative of formula (Ia) according to claim 1, or Use of the compound in salt form. 6) Trans-in the production of pharmaceuticals with antidepressant effects
Use of 3,4-diphenylpiperidine. 7) Formula I: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) [In the formula, (C_1-C_3)-alkyl, trifluoromethyl, trichloromethyl, hydroxyl, C_1-C_4-alkoxy, halo-(C_1-
C_4)-alkoxy, phenyloxy, phenyl-(
C_1-C_3)-alkoxy, acyloxy with up to 4 carbon atoms, nitro, N,N-dialkylamino with 1 to 4 carbon atoms in each alkyl group, morpholino or C_1-C_4-alkylsulfonyl , or one of the groups X and Y is hydrogen and n
is 1, 2 or 3] or physiologically acceptable salts of these compounds, provided that substituent X
and compounds in which one of Y is C_1-C_4-alkoxy and the other is hydrogen, and n is 2. 8) Compounds according to claim 7 which exist in enantiomeric form. 9) The reducing agent for the amide functional group of piperidone is expressed as Formula II: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) [In the formula, X, Y and n have the meanings in Formula I]
piperidone, thereby obtaining the corresponding piperidine I of similar cis- or trans stereochemistry to the starting piperidone, optionally converting the reaction product into a physiologically acceptable salt. range 7th
A method for producing the compound described in section.